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Enzyme

Total Therapy XVII for Leukemia

Phase 2 & 3

Waitlist Available

Led By Hiroto Inaba, MD, PhD

Research Sponsored by St. Jude Children's Research Hospital

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Diagnosis of B- or T-ALL or LLy by immunophenotyping

LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by morphology and flow cytometry. If any of these show ≥25% blasts, patient will be considered to have leukemia

Must not have

Inability or unwillingness of research participant or legal guardian/representative to give written informed consent

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from baseline to week 49 continuation treatment (up to 6 months after last patient completes week 49 continuation)

Awards & highlights

No Placebo-Only Group

Summary

This trial is using novel precision medicine strategies based on inherited and acquired leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy).

Who is the study for?

This trial is for children aged 1-18 with newly diagnosed B-cell or T-cell acute lymphoblastic leukemia (ALL) or lymphoma, who haven't had much treatment before. They must be able to give consent and not be pregnant, breastfeeding, or unwilling to use contraception.

What is being tested?

The study tests a combination of drugs like Calaspargase Pegol and Bortezomib among others, aiming to improve survival rates by targeting specific genetic features of the leukemia. It includes precision medicine strategies and therapies such as CAR T cells for certain patients.

What are the potential side effects?

Potential side effects include allergic reactions to medication components, nerve damage from drugs like Vincristine, increased risk of infections due to immune system suppression, liver problems from medications like Methotrexate and Mercaptopurine.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have been diagnosed with a type of leukemia.

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My cancer has less than 25% tumor cells in my bone marrow and blood.

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I am between 1 and 18 years old.

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I have been diagnosed with mixed phenotype acute leukemia (MPAL).

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I cannot or do not want to give my consent to participate.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ at 6 months after the last randomized patient completes continuation treatment (week 120).

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~at 6 months after the last randomized patient completes continuation treatment (week 120).

This trial's timeline: 3 weeks for screening, Varies for treatment, and at 6 months after the last randomized patient completes continuation treatment (week 120). for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype

Event-free survival of ALL patients (EFS)

Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation

Secondary study objectives

5-year OS of LLy patients

5-year overall survival (OS) of ALL patients compared to historical controls

Change in bone mineral density (BMD) in the tibia

+10 more

Other study objectives

5-year EFS of MPAL patients

5-year OS of MPAL patients

Log odds ratio of pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy)

+4 more

Side effects data

From 2022 Phase 3 trial • 402 Patients • NCT03110562

43%

Weight decreased

29%

Cough

29%

Thrombocytopenia

29%

Nausea

29%

Decreased appetite

21%

Fatigue

21%

Anaemia

21%

Constipation

21%

Diarrhoea

14%

Neuropathy peripheral

14%

Oedema peripheral

14%

Pneumonia

14%

Paraesthesia

14%

Cataract

14%

Vomiting

14%

Headache

Fungal skin infection

Urinary tract infection

Asthma

Disturbance in attention

Respiratory syncytial virus infection

Neutropenia

Peripheral swelling

Mental status changes

Lower respiratory tract infection

Hyperthyroidism

Back pain

Pain in extremity

Hyponatraemia

Skin lesion

Oropharyngeal pain

Pyrexia

Cardiac failure

Hepatitis

Pharyngitis

Pollakiuria

Non-cardiac chest pain

C-reactive protein increased

Taste disorder

Haemorrhagic transformation stroke

Abdominal pain

Insomnia

Dyspepsia

Haemoglobin decreased

Infection

Hyperglycaemia

Toothache

Ecchymosis

Upper respiratory tract infection

Nasopharyngitis

Viral infection

Hypertension

Muscular weakness

Bronchiectasis

Basal cell carcinoma

Hypophagia

100%

80%

60%

40%

20%

Study treatment Arm

SdX Arm: Selinexor + Dexamethasone

SVdX Arm: Selinexor + Bortezomib + Dexamethasone

SVd Arm: Selinexor + Bortezomib + Dexamethasone

Vd Arm: Bortezomib + Dexamethasone

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

7Treatment groups

Experimental Treatment

Group I: T-ALL and T-LLy, Standard-riskExperimental Treatment18 Interventions

Induction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Continuation (120 wks). During Remission Induction therapy, prednisone dose is 60mg/m\^2 and 3 doses daunorubicin are given. Dasatinib is given for patients with Ph+ and those with ABL-class fusion. Ruxolitinib is given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5% and all patients with ETP and T/M MPAL and LLy patients who don't qualify for complete response at end of Remission Induction. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD ≥ 5%. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, dexamethasone, doxorubicin, nelarabine, thioguanine.

Group II: T-ALL and T-LLy, High-riskExperimental Treatment21 Interventions

Induction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Reintensification. During Remission Induction therapy, prednisone dose is 60mg/m\^2 and 3 doses daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib given as done for patients with standard-risk T-ALL but are discontinued in Reintensification therapy. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, etoposide, dexamethasone, clofarabine, vorinostat, idarubicin, nelarabine, thioguanine..

Group III: B-ALL and B-LLy, Standard-riskExperimental Treatment18 Interventions

Induction (6wks), Early Intensification (4wks), Consolidation (8wks) and Continuation (120 wks). Remission Induction: Prednisone dose is 40mg/m\^2 and 2 doses daunorubicin are given. Dasatinib: given for patients with Ph+ and those with ABL-class fusion. Ruxolitinib: given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5%, LLy patients who don't qualify for complete response at end of Remission Induction and all patients with ETP and T/M MPAL. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD \>5%. Blinatumomab will be given to patients with residual disease at the end of induction (≥0.01% and \<1%), certain genetic subtypes and Down syndrome. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, thioguanine, methotrexate, dexamethasone, doxorubicin

Group IV: B-ALL and B-LLy, Low-riskExperimental Treatment15 Interventions

Patients with low-risk B ALL and LLy will have Induction (6 weeks), Consolidation (8 weeks), and Continuation (120 weeks). During Remission Induction therapy, prednisone dose is 40mg/m\^2 and 1-2 doses of daunorubicin (based on day 8 peripheral blood MRD in patients with ETV6-RUNX1 or hyperdiploid) are given. Dasatinib is given for patients with ABL-class fusion. Blinatumomab will be given to patients with certain genetic subtypes and those with Down syndrome. Interventions: Prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, thioguanine, methotrexate, dexamethasone, blinatumomab.

Group V: B-ALL and B-LLy, High-riskExperimental Treatment19 Interventions

Induction (6 weeks), Early Intensification (4 weeks), Consolidation (8 weeks), and Immunotherapy (chimeric antigen receptor \[CAR\] T cells). Patients who do not respond to Immunotherapy will receive Reintensification therapy. During Remission Induction therapy, prednisone dose is 40mg/m\^2 and 2 doses of daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib are given as done for patients with standard-risk B-ALL but are discontinued in Immunotherapy and Reintensification therapy. Blinatumomab will be given to patients who are not able to receive CAR T cell therapy and patients with certain genetic subtypes and those with Down syndrome. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, etoposide, dexamethasone, clofarabine, thioguanine, methotrexate.

Group VI: ALL, CEP72 T/T, VincristineExperimental Treatment1 Intervention

Patients with the CEP72 rs904627T/T genotype (\~16% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive either 1.5 mg/m\^2 or 1 mg/m\^2 of vincristine after Continuation Week 1. Patients in low- risk will complete vincristine in Week 49 and those in standard/high-risk will complete in Week 101. Intervention: vincristine.

Group VII: ALL, CEP72 C/T or C/C, VincristineExperimental Treatment4 Interventions

Patients with either a CEP72 rs904627 C/T or C/C genotype (\~84% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive vincristine (2 mg/m\^2 per dose except during Reinduction I and Reinduction II when 3 weekly doses of 1.5 mg/m\^2 will be given) and dexamethasone pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation Treatment. Patients at low-risk will complete vincristine in Week 49. Interventions: vincristine, dexamethasone, methotrexate, mercaptopurine.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Bortezomib

2005

Completed Phase 3

~1410

Idarubicin

2014

Completed Phase 4

~4370